The overall objectives of our research are bioactivity guided isolation and characterization of non-nucleoside antiviral agents derived from natural products and to evaluate the ability of these agents to inhibit viral replication in vitro and eventually in vivo. The present proposal is a continuation of the grant funded from September 30, 1989. We have isolated and characterized several compounds from Phyllanthus niruri which inhibit reverse transcriptase (RT) and some of which are effective against human immunodeficiency virus HIV-1 IIIB infection in Sup-T1 cells without any apparent toxicity to the cells. Other fractions of P. niruri which also show strong inhibition of RT are currently being purified prior to chemical characterization and testing for their effect on HIV-1 infection in Sup T-1 cells. Extracts of Phyllanthus tenellus, a species related to P. niruri, discovered in our separate studies on plants with antiviral activity against hepatitis B and related woodchuck hepatitis viruses, showed strong inhibition of RT. We propose to fractionate P. tenellus extract to isolate and elucidate the chemical structures of the active compounds in order to understand the structure-activity relationship in the HIV inhibitory components of two species of plants in the same genus. As a complementary approach we also propose to study four plants of a different genus, Terminalia: T. bellerica, T. catappa, T. mulleri, and T. nitens (all of which have been used medicinally in various parts of the world), the extracts of which strongly inhibit RT. Using the procedure that we have established for bio-activity guided separation of HIV inhibitory components of P. niruri, we plan to isolate and chemically characterize the active compounds from the four Terminalia spp. A comparison of the HIV inhibitory components within each genus and between two genuses may provide us with new non-nucleoside lead structures useful for therapy alone or in combination with other drugs presently in use to combat HIV infection. They may also provide us valuable information for the identification of structural features which enhance HIV inhibitory activity and those which decrease cellular toxicity, which will be of great benefit in obtaining semisynthetic or even total synthetic agents effective against HIV.